Transcription factors that regulate insulin sensitivity in the liver and metabolic syndrome

抄録

Liver plays a central role in energy metabolism depending upon nutritional states and hormones. Since long-term regulation of carbohydrate and lipid metabolisms is controlled at the transcriptional level, hepatic nutritional transcription factors play a pivotal role in energy metabolism. SREBP-1c has been established as a transcription factor that controls synthesis of fatty acids and triglycerides based upon our data from SREBP-1c transgenic and knockout mice. SREBP-1c also regulates insulin sensitivity via direct regulation of IRS-2, a key insulin-signaling molecule in the liver. Nutritional induction of hepatic SREBP-1c by dietary carbohydrates and saturated fatty acids well explains how liver shifts metabolism from glycogen synthesis to lipogenesis in the feeding cycle. To excess, SREBP-1c activation contributes to components of metabolic syndrome such as dyslipidemia, diabetes, fatty liver, and insulin resistance, and finally leading to atherosclerosis as observed in our murine models. Meanwhile, we have identified TFE3 as a strong activator of insulin signaling. TFE3 transcriptionally activates IRS2 and diversely participates insulin signaling and markedly ameliorates diabetes in different models. TFE3 and FOXOs synergistically activate, and SREBP-1c competitively suppresses IRS-2 promoter. Collectively, these energy transcripton factors regulate carbohydrate-lipid metabolism, insulin signaling, and might be involved in metabolic syndrome and diabetes. Thus, these factors could be future therapeutic targets. [J Physiol Sci. 2006;56 Suppl:S18]